APPLICANT'S ABSTRACT: The worldwide pandemic of Acquired Immunodeficiency Syndrome (AIDS) has had a tremendous social and economic impact in many parts of the world and while an impressive amount of information is available on the biology of the human immunodeficiency virus (HIV) and the host response to this retrovirus, the predictions for future control of this disease remains uncertain. The onset of clinical symptoms of AIDS is quite variable among HIV+ individuals with a mean incubation time of 5-10 years following seroconversion. Individual variation in the progression of HIV infection to clinical AIDS has been described to differences in the level of virulence. Individual variation in the progression of HIV infection to clinical AIDS has been ascribed to differences in the level of virulence for different isolates of HIV and to a number of possible cofactors which could affect HIV replication or immune responses during the course of disease. Ethanol (EtOH) has detrimental effects on the immune system and chronic abuse of EtOH has been suggested to be a possible cofactor which could enhance susceptibility to HIV and/or the subsequent development of AIDS. The development of the pathogenic process in AIDS is associated with inappropriate immune activation involving a selective defect in T-helper cell (Th1) responses mediated by interleukin-2 (IL-2) and interferon-g (IFN-g) and a predominance of Th2- responses mediated by interleukin-4, -5, -6, and -10. There is sufficient circumstantial evidence concerning the regulation of Th1 and Th2 responses by the chronic use of EtOH in humans and animals. However, direct evidence for the effects of EtOH on the Th1 and Th2 function and its potential contribution to the imbalance in Th1 and Th2 cell function and disease progression in AIDS is still lacking. The overall research goals for our laboratory are to determine the mechanisms of EtOH immune dysfunction in the CD4+ Th (Th) cell compartment and the subsequent imbalance in the Th1 and Th2 type responses with the ultimate goal being to develop cytokine therapy to reconstitute the immune system and serve as the much needed part of comprehensive therapeutic strategy for HIV disease. In this proposal we will study the effects of EtOH on (i) the development of murine Th1 and Th2 functions in normal mice and (ii) the existing imbalance of Th1 and Th2 responses associated with HIV disease, using a mouse AIDS infection model. Initially we will determine if EtOH affects (a) differentiation of Th cells to Th1 and Th2 cells or (b) the preexisting differentiated Th1 and Th2 cells. Using mice that are highly and moderately resistant we will determine if the modulation by EtOH of Th1 and Th2 responses leads to increased susceptibility to the MAIDS infection. Opportunistic infections are one of the important clinical aspects of AIDS and resolving them requires an appropriate Th1 and Th2 balance. Since both HIV/MAIDS diseases are associated with compromised cell mediated immunity (CMI), we will evaluate, in the mice model, the effects of EtOH on susceptibility to opportunistic infection by Listeria monocytogenes, a pathogen requiring cell mediated immune (Th1) responses for clearance. AIDS as well as chronic EtOH consumption are accompanied by the depletion of intracellular glutathione (GSH) leading to oxidative stress. Oxidative stress/GSH depletion can modulate HIV replication and T cell immune function by affecting T cell receptor mediated signaling and activation of redox- regulated transcription factors. In mice, EtOH causes depletion and oxidative stress sensitive transcription factors NF-kB and AP-1, in the development and/or activation of Th1 and Th2 responses in normal and MAIDS infected mice.